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A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms (DALIAH)

Primary Purpose

Polycythemia Vera, Essential Thrombocythemia, Primary Myelofibrosis

Status
Completed
Phase
Phase 3
Locations
Denmark
Study Type
Interventional
Intervention
PegIntron
Pegasys
PegIntron
Pegasys
Hydrea
Sponsored by
Thomas Stauffer Larsen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polycythemia Vera

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female > 18 years of age
  • Newly diagnosed, or previously diagnosed untreated patients with ET, PV or PMF including prefibrotic myelofibrosis according to the WHO classification
  • Active disease defined by one of the following criteria:
  • need for phlebotomy
  • leukocytosis > 10 mia/l
  • thrombocytosis > 400 mia/l
  • constitutional symptoms (fatigue, weight loss, night sweats or fewer > 38 degrees celsius)
  • Pruritus
  • splenomegaly causing symptoms
  • previous thrombosis

Exclusion Criteria:

  • Fertile women without a negative pregnancy test
  • Other malignant disease within last 5 years
  • ECOG performance score >/= 3
  • Creatinine > 2x ULN
  • Bilirubin > 1.5x ULN
  • ALAT > 3x ULN
  • Previous psychiatric disorder (depression)
  • active autoimmune disease
  • Uncontrolled thyroid disease

Sites / Locations

  • Dept of Hematology, Aalborg hospital
  • Dept. of Hematology, Aarhus University Hospital
  • Dept of Hematology, Esbjerg Hospital
  • Dept of Hematology, Herlev Hospital
  • Dept of Hematology, Holstebro Hospital
  • Dept of Hematology, Rigshospitalet
  • Dept of hematology, Odense University Hospital
  • Dept. of Hematology, Roskilde Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

PegIntron <= 60 years

Pegasys <= 60 years

PegIntron > 60 years

Pegasys > 60 years

Hydroxyurea > 60 years

Arm Description

In patients <= 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.

In patients <= 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.

In patients < 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.

In patients > 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.

Capsule Hydrea 500-2000 mg orally QD or BID

Outcomes

Primary Outcome Measures

molecular response (changes from baseline)
Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.

Secondary Outcome Measures

toxicity (discontinuation of therapy due to intolerability)
The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability
Quality of life (changes from baseline)
Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF
Histopathological response (changes from baseline)
A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.
Sustained molecular response (changes from level at time of discontinuation of therapy)
investigation of the sustainability of an obtained molecular remission (< 1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.
Neutralizing antibodies against PegIntron and Pegasys
Proportion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.
hematological response
Hematological response will be evaluated according to the ELN guidelines.

Full Information

First Posted
June 23, 2011
Last Updated
April 19, 2022
Sponsor
Thomas Stauffer Larsen
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1. Study Identification

Unique Protocol Identification Number
NCT01387763
Brief Title
A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
Acronym
DALIAH
Official Title
Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
January 2012 (undefined)
Primary Completion Date
June 2020 (Actual)
Study Completion Date
June 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Thomas Stauffer Larsen

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study is to compare the efficacy and toxicity including quality of life of two types of low-dose interferon alpha compounds (PegIntron and Pegasys) with hydroxyurea (Hydrea), and to investigate the occurence of neutralizing antibodies against recombinant interferon.
Detailed Description
Chronic myeloid neoplasms (CMPN) consists of three main entities, polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These three disorders have many overlapping clinical features. The diseases are clonal stem cell disorders characterized by a chronic excess production of mainly mature myeloid cells. The excess production of clonal red cells (in PV), platelets (in PV, ET and PMF) and leukocytes (mainly PV and PMF)leads to a highly increased risk of thrombosis. Patients may also suffer from constitutional symptoms, pruritus and splenomegaly. An inherent feature of these diseases are the risk of ET and PV of transformation to myelofibrosis and a risk of both ET, PV and PMF of leukemic transformation. In 2005 major breakthrough in our understanding of the molecular pathophysiology was achieved with the identification of the JAK2 V617F mutation which is present in almost all patients with PV (98%) and about half of patients with ET and PMF. This somatic gain-of-function point mutation in the JAK2 tyrosine kinase leads to constitutive activation of the kinase. By this mechanism a clonal non-growth factor dependent myeloproliferation is established. Traditionally the excess platelet and white cell production in ET, PV and PMF has been treated with cytoreductive agents such as hydroxyurea and busulfan in order to normalize the blood counts and thereby reducing the risk of thrombosis. However, in younger patients there is a concern of the leukemogenic potential of these agents. In younger patients an alternative treatment option is recombinant pegylated interferon alpha (IFN-alpha), which has demonstrated high clinical efficacy and has no leukemogenic potential. Within recent years IFN-alpha has demonstrated a capacity of inducing deep molecular remission (evaluated by JAK2 V617F qPCR) and normalisation of bone marrow morphology. These remissions have been sustained for up to 3 years after discontinuation of IFN-alpha therapy. Accordingly a perspective of changing the natural history of these disorders towards myelofibrosis and ultimately acute leukemia has emerged. However toxicity has been a major issue and drop-of rates have been reported consistently around 25 %. It is well known from other diseases (e.g multiple sclerosis and hepatitis) that some patients develop neutralizing antibodies against IFN-alpha. This issue is however only scarcely investigated in CMPN and has never been tested in a prospective design. The purpose of this study is to compare the efficacy (hematological and molecular) and toxicity profile of two different recombinant interferon alpha products, IFN-alpha2a and IFN-alpha2b in a prospective randomized design. In patients over the age of 60 there will be a third study arm with hydroxyurea. In order to decrease drop out rates and thereby increasing response rates patients will be started of at a low-dose of IFN-alpha. If patients fail to respond or looses their response and develops neutralizing antibodies against IFN-alpha therapy will be stopped. If patients have a sustained deep molecular response (below 1 % JAK2 V617F mutated alleles for 12 months) therapy will be stopped to asses the sustainability of the remission off therapy.Patients over the age of 75 and intolerant or resistant to hydroxyurea will be offered rescue treatment with orally busulfan (Myleran). As an important part of the study quality of life will be investigated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycythemia Vera, Essential Thrombocythemia, Primary Myelofibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
202 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PegIntron <= 60 years
Arm Type
Active Comparator
Arm Description
In patients <= 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.
Arm Title
Pegasys <= 60 years
Arm Type
Active Comparator
Arm Description
In patients <= 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
Arm Title
PegIntron > 60 years
Arm Type
Active Comparator
Arm Description
In patients < 60 years PegIntron is started at low-dose 35 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 96 micrograms weekly.
Arm Title
Pegasys > 60 years
Arm Type
Active Comparator
Arm Description
In patients > 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
Arm Title
Hydroxyurea > 60 years
Arm Type
Active Comparator
Arm Description
Capsule Hydrea 500-2000 mg orally QD or BID
Intervention Type
Drug
Intervention Name(s)
PegIntron
Other Intervention Name(s)
Pegylated interferon alpha 2b
Intervention Description
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
Intervention Type
Drug
Intervention Name(s)
Pegasys
Other Intervention Name(s)
Pegylated interferon alpha 2a
Intervention Description
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
Intervention Type
Drug
Intervention Name(s)
PegIntron
Other Intervention Name(s)
Pegylated interferon alpha 2b
Intervention Description
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
Intervention Type
Drug
Intervention Name(s)
Pegasys
Other Intervention Name(s)
Pegylated interferon alpha 2a
Intervention Description
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
Intervention Type
Drug
Intervention Name(s)
Hydrea
Other Intervention Name(s)
hydroxyurea, hydroxycarbamide
Intervention Description
Capsule Hydrea 500-2000 mg orally QD or BID
Primary Outcome Measure Information:
Title
molecular response (changes from baseline)
Description
Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.
Time Frame
18, 36 and 60 months
Secondary Outcome Measure Information:
Title
toxicity (discontinuation of therapy due to intolerability)
Description
The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability
Time Frame
18 months
Title
Quality of life (changes from baseline)
Description
Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF
Time Frame
4, 12, 24, 36, 48 and 60 months
Title
Histopathological response (changes from baseline)
Description
A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.
Time Frame
36 and 60 months
Title
Sustained molecular response (changes from level at time of discontinuation of therapy)
Description
investigation of the sustainability of an obtained molecular remission (< 1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.
Time Frame
12, 24 and 36 months
Title
Neutralizing antibodies against PegIntron and Pegasys
Description
Proportion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.
Time Frame
24 months
Title
hematological response
Description
Hematological response will be evaluated according to the ELN guidelines.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female > 18 years of age Newly diagnosed, or previously diagnosed untreated patients with ET, PV or PMF including prefibrotic myelofibrosis according to the WHO classification Active disease defined by one of the following criteria: need for phlebotomy leukocytosis > 10 mia/l thrombocytosis > 400 mia/l constitutional symptoms (fatigue, weight loss, night sweats or fewer > 38 degrees celsius) Pruritus splenomegaly causing symptoms previous thrombosis Exclusion Criteria: Fertile women without a negative pregnancy test Other malignant disease within last 5 years ECOG performance score >/= 3 Creatinine > 2x ULN Bilirubin > 1.5x ULN ALAT > 3x ULN Previous psychiatric disorder (depression) active autoimmune disease Uncontrolled thyroid disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas S Larsen, MD PhD
Organizational Affiliation
Dept. of Hematology, Odense University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dept of Hematology, Aalborg hospital
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark
Facility Name
Dept. of Hematology, Aarhus University Hospital
City
Aarhus
ZIP/Postal Code
8000
Country
Denmark
Facility Name
Dept of Hematology, Esbjerg Hospital
City
Esbjerg
ZIP/Postal Code
6700
Country
Denmark
Facility Name
Dept of Hematology, Herlev Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Facility Name
Dept of Hematology, Holstebro Hospital
City
Holstebro
ZIP/Postal Code
7500
Country
Denmark
Facility Name
Dept of Hematology, Rigshospitalet
City
København
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Dept of hematology, Odense University Hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Facility Name
Dept. of Hematology, Roskilde Hospital
City
Roskilde
ZIP/Postal Code
4000
Country
Denmark

12. IPD Sharing Statement

Learn more about this trial

A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms

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